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Three interesting recent papers add further support to the proposition that herpes simplex virus type 1 (HSV1) plays a major role in many cases of Alzheimer’s disease (AD). The first, by Piacentini et al. (1), found that HSV1 infection of primary cultures of rat embryonic neurons causes hyperexcitability and disrupts intraneuronal Ca2+ homeostasis, as shown by the influx of large amounts of Ca2+. These changes, caused by virus binding to the neuronal membranes, lead to Ca2+-dependent APP phosphorylation and increased intracellular Aβ production—the latter in agreement with our finding that HSV1 increases Aβ accumulation in cultured cells and in brains of infected mice, and increases levels of β- and γ-secretase (2). (The increase in β-secretase which leads to the increased Aβ has since been shown to occur via activation of PKR and eIF2α [Ill-Raga et al., under revision]). As Piacentini et al. point out, loss of Ca2+ homeostasis and its effects on APP metabolism are notable features of AD, and they state that their findings “are compatible with the co-factorial role for HSV1 in the pathogenesis of AD suggested by previous findings” (1). Another paper by the same group (3) describes HSV1-induced APP processing that generates multiple neurotoxic fragments which, they speculate, would accumulate on repeated reactivation of HSV1, and thus play a co-factorial role in AD.

Piacentini et al. attribute Aβ production to the HSV1-induced hyperexcitability and Ca2+-dependent APP phosphorylation, but it was not directly caused by virus-membrane binding, for they found that UV-inactivated HSV1 (which binds to and enters cells but does not replicate) did not produce Aβ. In fact, our studies on Vero cells infected with mutant HSV1 indicate that initiation of Aβ formation, and of AD-like tau phosphorylation (p-tau), occur during or after the viral IE protein synthesis stage that immediately precedes viral DNA replication (in preparation); consistently, we found that antiviral agents that stop HSV1 DNA synthesis greatly decrease virus-induced increases in Aβ and p-tau in both Vero and human neuroblastoma cells. The stage(s) at which viral damage occurs is relevant to the possible usage of anti-herpes agents for treating AD, because these agents would prevent HSV1-induced Aβ and p-tau formation only if such damage depends on viral DNA synthesis. However, by preventing HSV1 replication, anti-herpes agents would stop formation and spread of new viruses, thereby precluding any virus binding to the membranes of uninfected cells, and, in fact, reducing greatly all types of viral damage—while causing no harm to normal cell components.

The second paper, by Lukiw et al. (4), investigated micro-RNA-146a, an miRNA associated with innate immunity. Expression of this miRNA increases after onset of neuropathology in AD transgenic mouse models, and its levels are higher in certain regions of AD brains than in those of age-matched controls (5). Lukiw et al. (4) found that HSV1 infection upregulated miRNA-146a in co-cultures of primary neuronal and glial cells, and that the antiviral agent acyclovir, which specifically targets replicating virus, significantly reduced levels of this miRNA. The same occurred with soluble Aβ42 (although the authors seem not to have checked quantitatively for a toxic effect of Aβ42 rather than a direct antiviral effect). The authors suggest that Aβ42 might thus act as an antiviral agent in HSV1-infected brains, broadly in line with the study by Soscia et al. (6) proposing that the peptide has antimicrobial action. The seemingly paradoxical properties (protective and destructive) of Aβ and its products could be explained, as we suggested, by its having initially a protective action but subsequently being overproduced (7). An alternative possibility—that it is induced by the virus to aid its own replication—seems less likely in view of these data.

The third paper, by Porcellini et al. (8), suggests that the strong polymorphism association of eight genes with AD results in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and Aβ deposition. Data from our lab, and from studies of others on HSV1-infected ApoE-transgenic mice, suggest that ApoE modulates the severity of damage caused by HSV1. Perhaps in humans, ApoE determines also the age at which the virus travels from the peripheral nervous system to the brain, with entry occurring earlier in ApoE-ε4 carriers. However, it seems not to determine susceptibility to infection of brain, as human carriers of all ApoE genotypes can harbor HSV1 in brain (9), and in HSV1-infected ApoE-ε3-transgenic mice, the virus does enter the brain, albeit at lower rates than in ApoE-ε4 animals (10,11). Nonetheless, the hypothesis of Porcellini et al., like the data cited here, supports a role for HSV1 (in concert with ApoE-ε4) in AD. Hopefully, these and previous studies will encourage the AD community at least to ponder that possibility!